The Diabetes Mellitus (DM) is a metabolic disease caused by many etiological factors, the characteristic of which is chronic hyperglycemia, accompanied with glucose, lipid and protein metabolism disorders caused by the deficiency of insulin secretion and/or action. It is a clinical syndrome (a chronic, systematic or metabolic disease) caused by the interaction of hereditary factors and environmental factors. Most of the Diabetes Mellituses are caused by absolute or relative deficiency of insulin in human bodies and mainly characterized by hyperglycaemia. The diabetes is a lifetime disease.
Diabetes mellitus may be categorized into two subclasses: type I and type II. The type II diabetes is more dangerous and comprising over 90% of individuals suffering from diabetes. As the type II diabetes is often caused by obesity and lack of exercise, the incidence of Type II diabetes has increased rapidly in developed countries. The number of diabetes patients is expected to grow to over 200 millions in the world in 2010, and over 300 millions in 2025.
Generally, the type II diabetes is characterized by hyperglycemia, which causes metabolic disorders in vivo, and then develops into complications, referred to as metabolic syndromes, such as nervous system disease, kidney diseases, retinopathy, hypertriglyceridemia, obesity and cardiovascular disease. Diabetes is regarded as a fifth fatal disease in the world since it often causes complications in blood circulation and nervous system. On May 5th 2004, WHO reported that currently about 3.2 millions of death is caused by the diabetes-induced complications in the world every year. In most countries, diabetes has become one of the main causes of early death.
Diabetes is a clinical syndrome caused by the interaction between hereditary factors and environmental factors such as high fat diet, lack of exercise, obesity, aging and the like. It is caused by two pathogenic factors: insulin resistance and islet β cells failure. A variety of treating molecules targeting diabetes-related features have been found, and some medicaments have been developed for clinical treatment. For example, (1) sulfonylureas, which depolarize pancreatic islet β cells by inhibiting ATP-dependent potassium channel, thus leading to the opening of calcium channels, increasing Ca2+ influx of β cells and inducing the secretion of insulin; (2) biguanides, which may facilitate the intake of glucose by muscle tissues, accelerate anaerobic glycolysis, inhibit gluconeogenesis and reduce the output of liver sugar; (3) α-glucosidase inhibitors, which treat diabetes by inhibiting the activity of α-glucosidase in the digestive tract and delaying the digestion and absorption of carbohydrates; (4) thiazolidinediones (TZD), which may activate nuclear receptor PPARγ, regulate the differentiation of adipose cells, increase insulin sensitivity and the like. However, all of these medicaments are based on different targets and have some limitations.
At present, oral hypoglycemic drugs for treating Type II diabetes are typically combined administration of sulfonylureas and biguanides. However, sulfonylureas can be associated with primary or secondary failure during the course of treatment, and sometimes leading to hypoglycemia and obesity. Biguanides tend to induce hyper-lactic acid, nausea and diarrhea. TZD antidiabetic drugs regulate blood glucose metabolism by activating PPARγ and thus have some advantages in treating diabetes. However, many undesirable side effects of TZD drugs, such as cardiac enlargement, hemodilution and hepatotoxicity are gradually emerging in clinical applications. A lot of malpractices in which liver damage or even death may occur due to the use of TZD drugs have been reported. Therefore, there is a need to find one safer and more effective antidiabetic drug.
Metabolic syndrome is a disease caused by pathobolism. The pathophysiology basis of metabolic syndrome is carbohydrate, lipid and protein metabolism disorders. Clinical situations of patients are mainly hypertension, hyperglycemia or insulin resistance (although the blood glucose is not high), hyperinsulinemia, hyperlipemia, microalbuminuria, obesity—especially central obesity. The patients may also suffer from fatty liver, gallstone, hyperuricacidemia, arthrolithiasis, osteoporosis, artherosclerosis and the like because of the above three kinds of pathobolisms. Although metabolic syndrome will not threat life directly, it will result in other serious life-threatening diseases, such as cerebral apoplexy and coronary heart disease. Therefore, it is a disease which can not be neglected. The main indexes for the diagnosis of the metabolic syndrome are blood glucose, triglyceride, total cholesterol (TC), unsaturated free fatty acid (NFFA), and uric acid. If the above indexes exceed the normal level, one can be diagnosed of metabolic syndrome.
Metabolic syndrome is closely correlated to Type II diabetes, and can be considered as one important form of pre-diabetes. Metabolic syndrome mainly includes insulin resistance, hyperinsulinemia, impaired glucose tolerance, obesity, hypercholesteremia, abnormal metabolism of lipid, angiosclerosis, coronary artery disease, hypertension, hyperuricacidemia and arthrolithiasis, the clinical situations of which are mainly abdominal fat, scleratheroma dyslipidemia, hypertension, insulin resistance (accompanied with or without abnormal glucose tolerance), embolism, and inflammation. The development of metabolic syndrome is closely correlated to the occurance of cardiovascular disease and Type II diabetes, seriously threatening people's health. The therapy scheme of metabolic syndrome in most cases is that appropriate medicaments are selected according to the clinical symptoms, for example, lipidase inhibitors and serotonin reuptake inhibitors (SSRIs) may be used to reduce weight; fibrates and nicotinamides may be used to reduce lipid; biguanides, thiazolidinediones, α-glucosidase inhibitors may be used to improve insulin resistance or abnormal glucose tolerance; ACE inhibitors and α1 receptor blocker may be used to treat hypertension. However, since metabolic syndrome is usually associated with several clinical situations, a medicament having hypoglycemic, hypolipidemic effects as well as improving insulin resistance will show significant therapeutic effects for metabolic syndrome.
In summary, it is urgent to develop a new drug which has good effects in the prevention and treatment of diabetes or metabolic syndrome, and therefore improve the quality of life for various patients.